European Union gets it wrong on GMOS. Again.

Teosinte on the left, modern
corn on the right, a hybrid in

the center.

A European Union court just issued a new decision about GMOs. Disappointingly, this decision is likely to confuse rather than clarify this complex and contentious issue. The court announced that plants whose genomes have been modified with CRISPR technology, a very precise form of genome editing, are subject to the EU's very strict restrictions on genetically modified crops.

More specifically, the Court of Justice of the European Union (ECJ) decided that:

"Organisms obtained by mutagenesis are GMOs."

If we take this literally, then here’s a list of all the foods that have never been subjected to mutagenesis, and are therefore NOT GMO:

1. Salt
2. Wild boar
3. Wild blueberries

That’s it. (OK, maybe there are a few others.)

We have been modifying the genes of the foods we eat for millenia. Every loaf of organic, non-GMO bread is made from wheat that humans have modified since ancient times. Every glass of milk from your grass-fed, bovine-growth-hormone-free cow comes from a cow that humans have bred for centuries. All cows are genetically modified. Those delicious croissants you bought at the organic bakery? Sorry, those are GMOs, no matter how organic you think they are.

And corn? Have you seen what ancient corn, called teosinte, looks like? I encourage you to Google it (or see the image on this blog, above). Modern corn is the result of many generations of human-driven genetic modifications.

To be fair, the EU court recognized that many of our foods have been genetically modified for a long time, and that it might be impractical to remove all of them from our food supply. So they carved out an exception:

"varieties [of plants] obtained by means of mutagenesis techniques which have conventionally been used in a number of applications and have a long safety record are exempt...."

What's ironic here–though I'm confident that the EU court didn't mean this–is that by this definition, virtually all of the GMO crops in the U.S. are exempt. You see, we've been eating them for decades, and they have a phenomenal safety record.

Two years ago, the US National Academies of Sciences, Engineering, and Medicine issued a massive report that reviewed over 1,000 studies of GMOs. The bottom line: there are no health risks whatsoever from eating genetically modified foods.

Earlier gene editing technology sometimes added foreign genes to an organism, such as adding a bacterial gene to a plant. The EU court's new decision is intended to clarify that even if a foreign gene is not involved, plants bred using the newest form of gene editing (CRISPR technology) are nonetheless GMOs.

Banning GMOs doesn't make sense, and it never did. Genetic technology is just a tool, one that can be used for countless purposes, some of them highly beneficial–such as golden rice, which has the potential to prevent blindness in countries where many people depend on rice as their main staple food. If someone objects to a particular use of GM technology, such as Monsanto's use of it to create herbicide-resistant plants, that's something we can reasonably debate. But banning all GMOs is throwing out the baby with the bathwater.

Now if you'll excuse me, I've got to go out to my grill and see how my wild boar is doing. It might need a bit more salt.

CRISPR gene editing controversy - does it cause unexpected mutations?

Just over a month ago, a short paper appeared in Nature Methods saying that the gene editing technique known as CRISPR-Cas9 has a big problem: it creates unexpected mutations all over the genome. This was startling news for a technique that has been hailed worldwide as a dramatic breakthrough, not only because it is the easiest gene-editing method yet invented, but also because it is (supposedly) very precise.

This new paper, by Kellie Schaefer and colleagues, found hundreds of mutations (in experimental mice) that weren't supposed to be there. The results contradicted earlier studies that showed CRISPR caused very few of these "off-target" mutations. One of the authors, Stephen Tsang, commented that

"We feel it's critical that the scientific community consider the potential hazards of all off-target mutations caused by CRISPR."

Not surprising, the resulting news headlines were gloomy. The stock in three companies trying to commercialize gene editing–Editas Medicine, Intellia Therapeutics, and CRISPR Therapeutics–all fell sharply.  (Interestingly, the stocks started falling on May 24, and bottomed out on May 31. The paper appeared online on May 30.) Scientists involved with these companies quickly responded, arguing that the study was flawed, but of course those scientists have a lot of money at stake.

Who was right? Well, a new paper by Caleb Lareau and colleagues, just released in the bioRxiv preprint repository, re-examines the same data and concludes that CRISPR is just fine. I've read both papers so you don't have to. Here's what seems to be going on.

The study by Schaefer et al. used CRISPR-Cas9 to create mutations in two mice (called F03 and F05), and then sequenced their genomes. They also sequenced the genome of a third mouse, called FVB. All three mice were supposed to be genetically identical.

Then they compared all three genomes to a "reference" mouse to find mutations. (Aside: this is something my own lab does all the time, so I know the techniques well.) They found over 1,500 mutations in each mouse (which wasn't surprising, because the reference mouse differs from their 3 lab animals), but they found hundreds more mutations in the two CRISPR-edited mice. That was the main surprise from Schaefer's paper, and it's the basis for their claim that CRISPR causes numerous off-target mutations.

I had a big problem with this claim even before reading Lareau's paper. Just TWO mice? That's a ridiculously tiny sample. But I digress.

Lareau et al. pointed out, correctly, that Schaefer's conclusion depends on the mice being genetically identical. But what if the two CRISPR mice (F03 and F05) were closer to each other than to the third mouse, FVB? (It's analogous to comparing two siblings with a first cousin, although these mice are much more inbred than any humans.) In that case, the result falls apart.

Fortunately, Schaefer et al. made all their data available (props to them for doing that), so Lareau could answer this question quite precisely.

It turns out that F03 and F05 are much closer to each other than either one is to FVB.  Lareau discovered that the two CRISPR mice share thousands of mutations that FVB doesn't have.

What does this mean? Lareau and colleagues conclude that the "unexpected" mutations in the CRISPR-edited mice were already there before the experiment began, and were not caused by gene editing. As they put it,

"the CRISPR-treated embryos most likely already harbored these private SNPs and indels prior to nuclease treatment whereas the control mouse did not."

In other words, it seems highly unlikely that CRISPR gene editing caused hundreds of unexpected mutations in these mice.

Even though CRISPR is being over-hyped right now, it is nonetheless genuinely exciting technology. Nature Methods was probably too eager to publish a controversial result, an all-too-common problem with big-name journals, and they seem to have done a poor job managing peer review. (Aside: I'd love to see what the reviewers said. Did they miss the obvious problems, or did the journal editors ignore the reviewers? I doubt we'll ever know.)

A final note: this kerfuffle illustrates the tremendous value of rapid publication through pre-print archives. Lareau et al.'s paper appeared a few days ago (July 5) on bioRxiv, along with all the data they used to support their arguments. We'll probably see a journal version too, but that will take months. Getting this paper out faster was a win for science.

(Postscript: two of the authors on the bioRxiv paper have financial interests in CRISPR technology companies, which they disclosed in the paper. I have no financial interests in any of these companies.)